1. Field of the Invention
The present invention relates to a tumor cell-killing peptide and a pharmaceutical composition for treating a cancer comprising the tumor cell-killing peptide.
2. Description of the Related Art
Apoptosis is a fine-tuned mechanism to eliminate harmful, seriously damaged, or unnecessary cells in multi-cellular organisms. Apoptosis plays an important role to grow a normal cell, to maintain cell homeostasis, to prevent cancer and other diseases, and to protect a living body from viral or bacterial infection. Extensive lines of evidence indicate that the mitochondria act as regulators of apoptosis, and mitochondrial integrity is controlled by the Bcl-2 family proteins (1). Bcl-2 family members are divided into two main groups according to whether they promote or inhibit apoptosis. The anti-apoptotic members (e.g., Bcl-2 and Bcl-XL) possess four BH domains from BH1 to BH4, whereas the pro-apoptotic members (e.g., Bax and Bak) have three BH domains from BH1 to BH3. The BH3-only proteins (e.g., Bid, Noxa and PUMA) induce apoptosis by activating pro-apoptotic proteins like Bax and Bak or inhibiting anti-apoptotic proteins like Bcl-2 and Mcl-1 (2, 3).
Mouse Noxa, originally identified as a p53 target gene, plays a crucial role in apoptosis iduced by p53-dependent genotoxic stimuli (4-7). Two functional domains in Noxa, the BH3 domain and the mitochondrial targeting domain (MTD), have been identified (8). Recent studies indicate that the Noxa BH3 domain is crucial to the protein's ability to induce cell death by the selective inhibition of Mcl-1 and A1/Bfl-1 (1, 9-13). On the other hand, deletion of the Noxa MTD completely abolished cell death in HeLa cells mainly due to the loss of Noxa mitochondrial localization (8). Thus, it was thought that the MTD of Noxa delivers the BH3 domain of Noxa to the mitochondria, where the BH3 domain binds to Mcl-1 and A1/Bfl-1 resulting in inactivation of anti-apoptotic activities of Mcl-1 and A1/Bfl-1. This hypothesis suggests that cell death-inducing activity of Noxa solely depends on the capability of Noxa BH3 domain to inactivate Mcl-1 and A1/Bfl-1 function. However, Noxa mutant carrying mutation in BH3 domain cannot completely abolish the cell death-inducing activity of Noxa (6, 14), indicating that there is another potential killing domain in Noxa.